PROJECT SUMMARY (Project 1) Treatment of obesity requires an understanding of the mechanisms that regulate the short-term control of food intake, i.e., factors that reduce individual meal size (MS); prolong the time between two consecutive meals, known as the inter-meal interval (IMI); and result in reduction of body weight. The proposed effort will involve evaluation of the anti-obesity effects of the short-term satiety peptide, gastrin-releasing peptide (GRP) by testing the hypothesis that, if, in diet-induced obese rats, GRP is injected in low amounts and at highly specific gastrointestinal sites, it effectively and safely reduces MS and extends the IMI (i.e., increases satiety), resulting in reduction in body weight. There are three Specific Aims: Specific Aim I: Determine the specific gastrointestinal site(s) of action controlling MS, IMI length, and body weight (BW) by endogenous GRP released by a normal meal. Specific Aim II: Determine the specific gastrointestinal site(s) of action controlling MS, IMI length, and BW by exogenous GRP-10 (a COOH-terminal decapeptide of GRP) and GRP-29 (a large molecular form of GRP). Specific Aim III: Determine the specific gastrointestinal site(s) of action controlling MS, IMI length, and BW by endogenous GRP released by peptone. In addition, the safety of infusions of the peptides and antagonists will be evaluated by examining the morphology and weights of the specific gut sites of action following single and chronic infusions of GRP. We will test these three aims by innovative approaches, including use of (a) microvascular catheterization of the major arteries and their branches in the gut, (b) a sensitive enzyme immunoassay that determines the levels of GRP in response to meals; (c) immunohistochemical detection of Fos-like immunoreactivity, a marker for neuronal activation in the enteric neurons and in the dorsal vagal complex; (d) diet-induced obese rats; and (e) the automated BioDAQ feeding apparatus. This work will establish, in diet-induced obese rats, the specific site(s) of action regulating meal size, IMI, and BW by endogenous and exogenous GRP and will determine if GRP can be tested in humans as an anti-obesity medication.